Klotho was identified as the responsible gene in a mutant mouse line whose disruption results in a variety of
premature aging-related phenotypes. Nonetheless, the related mechanisms were still unknown. Many studies report that dietary
phosphate restriction and genetic ablation of
vitamin D pathways indirectly reverse
premature aging processes in these mice. Furthermore, transgenic overexpression of klotho in mice extends their life span through inhibition of
insulin and IGF1 signaling. We found that
intraperitoneal injection of recombinant soluble Klotho
protein at dose of 0.02 mg/kg every other day effectively extends the life span of kl/kl mice by 17.4%. Soluble Klotho administration also ameliorated
premature aging-related phenotype, such as growth retardation, premature thymus involution and
vascular calcification, and effectively enhanced urinary
phosphate excretion in kl/kl mice. Klotho treatment attenuated renal
fibrosis through down-regulation of
transforming growth factor-β signaling as well as reduced cellular senescence through down-regulation of p21-cip1
mRNA levels. In addition, soluble Klotho treatment significantly reduced both renal and aorta
calcium deposits. In conclusion, our study shows the therapeutic potential of soluble Klotho
protein to treat age-related disorders in mice.